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Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists.

ABSTRACT: Adenosine A(2A) receptor antagonists are psychomotor stimulants that also hold therapeutic promise for movement disorders. However, the molecular mechanisms underlying their stimulant properties are not well understood. Here, we show that the robust increase in locomotor activity induced by an A(2A) antagonist in vivo is greatly attenuated by antagonizing cannabinoid CB(1) receptor signaling or by administration to CB(1)(-/-) mice. To determine the locus of increased endocannabinoid signaling, we measured the amount of anandamide [AEA (N-arachidonoylethanolamine)] and 2-arachidonoylglycerol (2-AG) in brain tissue from striatum and cortex. We find that 2-AG is selectively increased in striatum after acute blockade of A(2A) receptors, which are highly expressed by striatal indirect-pathway medium spiny neurons (MSNs). Using targeted whole-cell recordings from direct- and indirect-pathway MSNs, we demonstrate that A(2A) receptor antagonists potentiate 2-AG release and induction of long-term depression at indirect-pathway MSNs, but not direct-pathway MSNs. Together, these data outline a molecular mechanism by which A(2A) antagonists reduce excitatory synaptic drive on the indirect pathway through CB(1) receptor signaling, thus leading to increased psychomotor activation.

SUBMITTER: Lerner TN

PROVIDER: S-EPMC2830732 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

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Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists.

Lerner Talia N TN Horne Eric A EA Stella Nephi N Kreitzer Anatol C AC

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100201 6

Adenosine A(2A) receptor antagonists are psychomotor stimulants that also hold therapeutic promise for movement disorders. However, the molecular mechanisms underlying their stimulant properties are not well understood. Here, we show that the robust increase in locomotor activity induced by an A(2A) antagonist in vivo is greatly attenuated by antagonizing cannabinoid CB(1) receptor signaling or by administration to CB(1)(-/-) mice. To determine the locus of increased endocannabinoid signaling, w ...[more]

PMID: 20147543

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Dataset Information

Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists.

Publications

Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists.

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